Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

Guo, Jingjing; Zhou, Huan‐Xiang

doi:10.7554/elife.18249

Cited by 18 publications

(17 citation statements)

References 40 publications

(64 reference statements)

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“…Overall, local quenching of subdomain dynamics in the MD and CTD regions of Hsp90 can be counterbalanced by strengthening of the inter-domain correlations and inter-molecular couplings. A similar pattern of dynamic changes induced by allosteric activators was detected in other protein systems that are primarily regulated by dynamically-driven allostery [ 103 – 105 ].…”

Section: Resultssupporting

confidence: 61%

Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains

2017

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A fundamental role of the Hsp90 and Cdc37 chaperones in mediating conformational development and activation of diverse protein kinase clients is essential in signal transduction. There has been increasing evidence that the Hsp90-Cdc37 system executes its chaperoning duties by recognizing conformational instability of kinase clients and modulating their folding landscapes. The recent cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex has provided a framework for dissecting regulatory principles underlying differentiation and recruitment of protein kinase clients to the chaperone machinery. In this work, we have combined atomistic simulations with protein stability and network-based rigidity decomposition analyses to characterize dynamic factors underlying allosteric mechanism of the chaperone-kinase cycle and identify regulatory hotspots that control client recognition. Through comprehensive characterization of conformational dynamics and systematic identification of stabilization centers in the unbound and client- bound Hsp90 forms, we have simulated key stages of the allosteric mechanism, in which Hsp90 binding can induce instability and partial unfolding of Cdk4 client. Conformational landscapes of the Hsp90 and Cdk4 structures suggested that client binding can trigger coordinated dynamic changes and induce global rigidification of the Hsp90 inter-domain regions that is coupled with a concomitant increase in conformational flexibility of the kinase client. This process is allosteric in nature and can involve reciprocal dynamic exchanges that exert global effect on stability of the Hsp90 dimer, while promoting client instability. The network-based rigidity analysis and emulation of thermal unfolding of the Cdk4-cyclin D complex and Hsp90-Cdc37-Cdk4 complex revealed weak spots of kinase instability that are present in the native Cdk4 structure and are targeted by the chaperone during client recruitment. Our findings suggested that this mechanism may be exploited by the Hsp90-Cdc37 chaperone to recruit and protect intrinsically dynamic kinase clients from degradation. The results of this investigation are discussed and interpreted in the context of diverse experimental data, offering new insights into mechanisms of chaperone regulation and binding.

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Section: Resultssupporting

confidence: 61%

Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains

2017

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“…Rogers et al (65) recently presented a scenario of dock and coalesce, with the docking and coalescing segments identified by experimental data for the effects of point mutations within the binding site on the binding rate constant. Interestingly, in addition to direct interactions within the binding site, allosteric effects by distally bound domains may also facilitate the dock-and-coalesce mechanism (33). …”

Section: Determination and Determinants Of Binding Mechanismsmentioning

confidence: 99%

Rate Constants and Mechanisms of Protein–Ligand Binding

Pang

Zhou

2017

Annu. Rev. Biophys.

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Whereas protein–ligand binding affinities have long-established prominence, binding rate constants and binding mechanisms have gained increasing attention in recent years. Both new computational methods and new experimental techniques have been developed to characterize the latter properties. It is now realized that binding mechanisms, like binding rate constants, can and should be quantitatively determined. In this review, we summarize studies and synthesize ideas on several topics in the hope of providing a coherent picture of and physical insight into binding kinetics. The topics include microscopic formulation of the kinetic problem and its reduction to simple rate equations; computation of binding rate constants; quantitative determination of binding mechanisms; and elucidation of physical factors that control binding rate constants and mechanisms.

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“…We measured the distances between these key residues in these structures and found that neither Y270F nor Y270E mutation brought obvious changes to it (Figure 6B). Since the binding of SUMO1 β-grasp domain (residues 20-92) induces structural changes in the active site of SENP1 and then enhances the enzyme activity of SENP1 (Chen et al, 2014;Guo and Zhou, 2016), the binding of SUMO to SENP1 is hence a prerequisite for SENP1 isopeptidase activity, and we wondered whether Y270 phosphorylation on SENP1 could regulate its isopeptidase activity via modulating its binding to SUMO-conjugated substrates. We performed the GST pull-down assay by using GST fused to the N-terminus of mature SUMO1 (1-97 aa) or SUMO3 (1-92 aa).…”

Section: Senp1 Y270 Phosphorylation Influences Its Binding Propensity...mentioning

confidence: 99%

TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

Cen

Gong

et al. 2022

Front. Cell Dev. Biol.

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Small ubiquitin-like modifier (SUMO) modification plays an important regulatory role in T cell receptor (TCR) signaling transduction. SUMO-specific proteases (SENPs) have dual-enzyme activities; they can both process SUMO precursors as endopeptidases and participate in SUMO deconjugation as isopeptidases. It remains unclear how the SUMO system, especially SENP1, is regulated by TCR signaling. Here, we show that Lck phosphorylates tyrosine 270 (Y270) of SENP1 upon TCR stimulation, indicating that SENP1 is a substrate of Lck. In vitro endopeptidase activity analysis showed that mutating SENP1 Y270 to either phenylalanine (F) to mimic the phosphorylation-defective state or to glutamate (E) to mimic the negative charge of tyrosine phosphorylation in the enzyme microenvironment did not change its endopeptidase activity towards pre-SUMO1. However, SENP1 Y270E but not Y270F mutation exhibited decreased endopeptidase activity towards pre-SUMO3. Through in vivo isopeptidase activity analysis by rescue expression of SENP1 and its Y270 mutants in a SENP1 CRISPR knockout T cell line, we found that SENP1 Y270F downregulated its isopeptidase activity towards both SUMO1 and SUMO2/3 conjugation by reducing SENP1 binding with sumoylated targets. While overexpression of SENP1 inhibited TCR-induced IL-2 production, overexpression of SENP1 Y270F enhanced it instead. In summary, TCR-induced Y270 phosphorylation of SENP1 may promote its isopeptidase activity and specifically decrease its endopeptidase activity against pre-SUMO3, which finely tunes activation of T cells.

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Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

Cited by 18 publications

References 40 publications

Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains

Atomistic simulations and network-based modeling of the Hsp90-Cdc37 chaperone binding with Cdk4 client protein: A mechanism of chaperoning kinase clients by exploiting weak spots of intrinsically dynamic kinase domains

Rate Constants and Mechanisms of Protein–Ligand Binding

TCR-Induced Tyrosine Phosphorylation at Tyr270 of SUMO Protease SENP1 by Lck Modulates SENP1 Enzyme Activity and Specificity

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